Genome-wide studies of linkage disequilibrium have revealed that most of the human genome is covered by blocks of varying length within which marker to marker linkage disequilibrium is very high. Each haplotype block is separated by recombination sites. There are usually only 3-6 haplotypes with greater than 5% frequency within each block. These haplotypes reflect descent from a single, ancient ancestral chromosome. The main advantage of haplotype methods for linkage and association studies is that these common haplotypes capture most of the information on genetic variation within these regions and the haplotypes can be identified using only a small number of SNPs, usually 3 to 8. Thus haplotype-based case-control studies can detect associations with disease or behavior without having to find and test every single variant in the region.[unreadable] [unreadable] We have genotyped two ethnically diverse population isolates, approximately 500 Finnish Caucasians and 400 Plains American Indians, for several candidate genes for alcoholism and anxiety. These include the chromosome 4 cluster of GABAA receptor genes and the neuropeptide galanin plus the 3 galanin receptor genes that have been implicated in response to severe stress. Haplotype-based analyses revealed that in men from these two populations there was an association between GABRA2 haplotypes and alcoholism that is mediated by harm avoidance (HA), a dimensional measure of anxiety (Enoch et al, 2006). In addition, in both populations (men and women) we found haplotype linkage to alcoholism in both GABRB1 and GABRG1. Moreover, alcoholism risks associated with GABRB1 and GABRG1 were additive. There was a galanin haplotype association with alcoholism in both populations that may also be mediated by anxiety (Belfer et al, 2006).The effects of galanin at GALR3 and not the other two receptors appear to be key for the association with alcoholism (Belfer et al, 2007). [unreadable] [unreadable] We have previously shown that the functional COMT Val158Met polymorphism is associated with trait anxiety in women (Enoch et al, 2003). We have recently shown that individuals with anxiety disorders comorbid with alcoholism and/or depression have the greatest proportion of COMT Met158 and BDNF Met66 alleles compared with individuals with pure anxiety, alcoholism, major depression or no diagnosis (Enoch et al, in press). We have previously shown in the Plains Indians that the COMT Met158 allele protects against smoking in women (Enoch et al, 2006). Preliminary analyses indicate that the CART gene is also associated with smoking in this population. Genotyping of SNPs and haplotype analyses are being undertaken in other alcoholism/anxiety candidate genes.